2-Oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor (FGFR) inhibitors

European Journal of Medicinal Chemistry
Xueqiang LiKe Ding

Abstract

A series of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were designed and synthesized as new irreversible inhibitors of the FGFR family. One of the most promising compounds 2l potently inhibited FGFR1/2/3 with IC50 values of 1.06, 0.84 and 5.38 nM, respectively, whereas its potency against FGFR4 was diminished by an order of magnitude. Compound 2l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung cancer cells, FGFR2-amplified SUM52 breast cancer cells and FGFR3-amplified SW780 bladder cancer cells with low nanomolar IC50 values, but was significantly less potent against four FGFR-negative cancer cell lines, with low micromolar IC50 values. Biological investigation also confirmed the irreversible binding of the molecule with the FGFR1-3 target kinases. Compound 2l may serve as a promising new lead for further anticancer drug discovery.

Citations

Sep 25, 2018·Expert Opinion on Therapeutic Patents·Francesco PetrellaLorenzo Spaggiari
Oct 28, 2018·Nature Reviews. Clinical Oncology·Masaru Katoh
Nov 5, 2019·Expert Opinion on Therapeutic Patents·Giuseppe MarsegliaRiccardo Castelli
Jan 31, 2020·Saudi Pharmaceutical Journal : SPJ : the Official Publication of the Saudi Pharmaceutical Society·Güneş Çoban, Fadime Aydın Köse
Nov 26, 2019·European Journal of Medicinal Chemistry·Feng-Tao LiuZhi-Hao Shi

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